The delivery of compounds through the skin provides many advantages. Primarily, transdermal delivery provides a comfortable, convenient, and noninvasive means for delivering drugs. By avoiding administration through the gastrointestinal tract, one may employ compounds which would otherwise be degraded, metabolically deactivated, or poorly absorbed. Additionally, one eliminates the complications of gastrointestinal irritation. Transdermal delivery using a continuous-release type of device also allows one to terminate administration immediately should the need arise, e.g., in the event of an adverse drug reaction, or over-elevation of drug plasma concentration.
Drug delivery devices may generally be classified as either "matrix" or "reservoir" in construction. A matrix or monolithic device generally comprises a drug-permeable solid polymer, having a drug dispersed throughout. Matrix devices may be formed from erodible or non-erodible polymers (transdermal devices are typically non-erodible). Reservoir devices generally comprise a depot of essentially pure drug (or drug with excipient) surrounded by a rate-controlling membrane, where the rate of drug diffusion through the membrane controls the rate of release. Combinations of matrix reservoirs with rate-controlling membranes have also been proposed. The typical design criteria are to provide a substantially constant and continuous release rate, and to provide a release rate capable of delivering a therapeutically effective amount of the compound. Additionally, the device must be non-irritating, and is preferably designed to be of a convenient size.
The conventional transdermal device is designed with the goal of delivering a therapeutic compound at a substantially constant rate ("zero-order" delivery). However, administration of some compounds at a constant, continuous rate may cause drug tolerance to develop. In order to prevent tolerance, a transdermal patch-type device must be removed periodically to interrupt continuous delivery. This in turn creates additional problems of patient compliance and design of the patch adhesive (which must adhere to the skin continuously), and fails to accommodate the patient's circadian rhythms.
Nitroglycerin is a vasodilator currently administered for coronary disorders, especially angina pectoris and congestive heart failure. As nitroglycerin cannot be administered orally, it is typically administered sublingually, or via transdermal patch. Commercially available patches, such as Transderm Nitro.RTM. and Nitro-Dur.RTM., provide essentially constant plasma concentrations of nitroglycerin over a 24 hour period, and are changed daily. However, recent studies suggest that continuous administration of nitroglycerin induces tolerance, with concomitant loss of efficacy in the patient.
There are a large number of patents disclosing drug delivery devices. General transdermal devices are disclosed in Zaffaroni, U.S. Pat. No. 3,742,951; 3,797,494; 3,854,480; 3,921,636; 3,996,934; Baker, U.S. Pat. No. 3,923,989; Gerstel et al, U.S. Pat. No. 3,964,482; Shaw et al, U.S. Pat. No. 4,650,484; 4,704,119; Gale, U.S. Pat. No. 4,661,105; 4,698,062; Eckenhoff et al, U.S. Pat. No. 4,717,568; and Magruder et al, U.S. Pat. No. 4,723,957. Devices for transdermal administration of nitroglycerin are disclosed by Blank, U.S. Pat. No. 4,533,540; Enscore et al, U.S. Pat. No. 4,559,222; Gale et al, U.S. Pat. No. 4,615,699; 4,681,454; 4,681,584; Leslie et al, U.S. Pat. No. 4,654,209; Theeuwes et al, U.S. Pat. No. 4,655,766; Andirola et al, U.S. Pat. No. 4,661,441; Wick, U.S. Pat. No. 4,751,087; Guse et al, U.S. Pat. No. 4,776,850; 4,778,678; Berry et al, U.S. Pat. No. 4,784,857; and Wagle et al, U.S. Pat. No. 4,786,282. However, these references do not teach transdermal delivery devices having a delayed onset of administration.